The broad and long-term objective of this project is to develop novel CB1 cannabinoid receptor positive allosteric modulators (PAMs) and validate their utility as a safe and effective pharmacotherapy for the treatment of glaucoma. Glaucoma is a multifactorial optic neuropathy with increased intraocular pressure (IOP) as a prominent risk factor and represents an unmet medical need. It is a leading cause of vision impairment and blindness, afflicting more than 60 million people worldwide and increasing in prevalence as population age. Though diverse therapeutic interventions are available, newer and better tolerated treatments for glaucoma are desirable. Orthosteric agonists of the CB1 cannabinoid receptor significantly reduce IOP clinically and experimentally and also impart neuroprotection. However, their development has been complicated by the need to avoid psychotropic side effects and abuse liability. Very recently, a new class of ligands has been identified for CB1 cannabinoid receptors -PAMs. These compounds enhance CB1 receptor activation at a secondary site by increasing the CB1 affinity of direct agonists and /or the ability of such agonists to induce CB1 receptor signaling. Because they are expected to affect the functioning of CB1 receptors that are already being activated endogenously, PAMs should avoid some of the risks of global ocular CB1 receptor activation, including off-target activation and desensitization that come with the use of an orthosteric agonist. PAMs have been the subject of intense study for several receptor classes but are only now coming to light for CB1. We provide here preliminary evidence that a topically applied CB1 PAM reduces IOP but does not have the abuse-liability associated with CB1 agonists. In this application, we propose to develop novel small molecule CB1 PAMs based on a 2-phenylindole scaffold. Through the synthesis and biochemical evaluations of about ~50 compounds/year over a period of 5 years, we anticipate (1) discovering CB1 PAMs with biochemical and electrophysiological EC50 values of < 50 nM, excellent solubility, and good eye penetration properties; (2) evaluating them as IOP reducers in a normotensive and hypertensive mouse models with CB1 knockout mice as controls and (3) evaluating them for promoting CB1-mediated retinal ganglion cells (RGC) neuroprotective potential in: (a) ocular hypertensive mouse models (microbead and Nee) and (b) an IOP-independent model of RGC loss after optic nerve injury (axotomy). Successful completion of the proposed drug discovery investigation by an interdisciplinary team of investigators will lead to the development of potent and efficacious CB1 PAMs and establish their role as an effective pharmacotherapy for glaucoma providing both decrease in IOP and neuroprotection to RGC.